Tuberculosis(TB) remains one of major causes of global mortality due to HIV/AIDS and multidrug-resistant TB (MDR-TB). Global control of TB is difficult because of the lack of an effective protective vaccine and sterilizing drugs. Since drug resistance likely increases, there i a pressed need to develop new vaccine or immuno- therapeutic. However, there is road-block for vaccine/therapeutic efforts since immune components of anti-TB immunity remain unknown in humans, and in-depth studies are needed to understand how HIV precisely destructs protective mechanisms leading to enhanced TB susceptibility and severity. Our decades-long studies elucidate multi-functional roles for Mtb-specific V?2V?2 T cells, the cell subset existin only in primates. Our new studies provide 1st evidence that dominant V?2V?2 T cells are protective, as they act very fast, traffic to lung within hours and confer anti-TB immunity. In addition, primate CD8+ T cells play a critical role in anti-TB immunity, and CD4+ T cells can function as innate-like cells to control very early TB dissemination while adaptively containing TB progression & sustaining multi-effector functions of CD8+ T and CD3- lymphocytes. We also show that human/macaque Th22 cells can carry membrane-bound IL-22 after de novo production and inhibit intracellular Mtb. Mechanically, rapid pulmonary trafficking/accumulation of vaccine-elicited CD4+/CD8+ Th1 clones appears to be a mechanism underlying T-cell-mediated protection against TB. This principle is supported further by our paralleled studies indicating that IL-2 administration during innate phase of Mtb infection rapidly expands pulmonary CD4+/CD8+ T effectors and confers anti-TB immunity. Furthermore, we showed that co-infection with AIDS virus and mycobacterium reduces the ability of innate/adaptive T cells to traffic/accumulate in the pulmonary compartment leading to enhanced susceptibility to HIV-related TB and reactivation. Notably, our collaborators for this project have exceptional track records of innate-like human CD1b-restricted T cells (22) and human innate immunity including VitD-induced anti-TB immunity, respectively. Our series of novel findings provide strong rationale to investigate immune mechanisms by which innate/adaptive components confer anti-TB immunity in immune competent and HIV-1-infected humans. We hypothesize that fast-acting innate T-cell populations can rapidly traffic to lung upon Mtb exposure, contain Mtb infection and bridge or synergize VitD-IL-32 innate immunity or adaptive T cells to sterilize Mtb and that HIV infection destructs these protective components. To test this hypothesis, we will recruit crucial human cohorts. Importantly, we will confirm human findings in relevant macaque TB and HIV+TB models. A success of this project will provide new concepts and mechanisms conceiving how the human host mounts sterilizing immunity against Mtb infection and how HIV destructs the sterilizing mechanisms.